1. Field of the Invention
The present invention provides heterocycle carboxamide derivatives. These compounds are useful as antiviral agents, in particular, as agents against viruses of the herpes family.
2. Technology Description
The herpesviruses comprise a large family of double stranded DNA viruses. They are also a source of the most common viral illnesses in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals, respectively. They also occasionally cause infections of the eye and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as retinitis, pneumonia, and gastrointestinal disease. VZV is the causative agent of chicken pox and shingles. EBV causes infectious mononucleosis. It can also cause lymphomas in immunocompromised patients and has been associated with Burkitt""s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. HHV-6 is the causative agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. HHV-7 disease association is unclear, but it may be involved in some cases of roseola. HHV-8 has been associated with Karposi""s sarcoma, body cavity based lymphomas, and multiple myeloma.
U.S. Pat. No. 5,792,774 discloses specific quinoline derivatives that are alleged to have therapeutic utility via inhibition of Phosphodiesterase IV esterase and/or Tumor Necrosis factor activity.
Despite the above teachings, there still exists a need in the art for novel compounds that demonstrate desirable antiviral activity.
In accordance with the present invention, novel compounds which demonstrate antiviral activity are provided. More specifically, the compounds are specific heterocycle carboxamide derivatives which are useful as antiviral agents, particularly against herpes viruses.
Even more specifically, the present invention provides a compound of formula I, 
wherein,
X is Cl, Br, F, CN or NO2;
G is
(a) C1-4alkyl which is fully saturated or partially unsaturated and is substituted by hydroxy, or
(b) C1-4alkyl substituted by NR1R2 or 4-tetrahydropyran;
R1 is C2-7alkyl substituted by hydroxy, C1-4alkoxy, aryl, or heteroaryl;
R2 is hydrogen or C1-7alkyl;
or R1 and R2 together with the nitrogen to which they are attached form (a) a morpholine which may be optionally substituted by aryl or C1-7alkyl; or (b) a pyrrolidine ring substituted by hydroxy;
W is a heterocycle of formula W1, W2, W3, W4, W5, W6, W7 or W8
A is CR4 or nitrogen;
B is CR5 or nitrogen;
D is
(a) xe2x80x94(CR13R14)axe2x80x94, where a is 2 or 3
(b) xe2x80x94(CR15R16)4xe2x80x94,
(c) xe2x80x94Yxe2x80x94CR13R14xe2x80x94CR13R14xe2x80x94,
(d) xe2x80x94CR13R14xe2x80x94Yxe2x80x94CR13R14xe2x80x94,
(e) xe2x80x94Yxe2x80x94CR13R14xe2x80x94Yxe2x80x94,
(f) xe2x80x94CR13R14xe2x80x94CR13R14xe2x80x94Yxe2x80x94,
(g) xe2x80x94Yxe2x80x94(CR15R16)nxe2x80x94,
(h) xe2x80x94Yxe2x80x94CR15xe2x95x90CR15xe2x80x94,
(i) xe2x80x94Yxe2x80x94CR15xe2x95x90Nxe2x80x94,
(j) xe2x80x94CR15xe2x95x90CR15xe2x80x94Yxe2x80x94,
(k) xe2x80x94Nxe2x95x90CR15xe2x80x94Yxe2x80x94,
(l) xe2x80x94(CR15R16)bxe2x80x94Nxe2x95x90CR15xe2x80x94, where b is 0 or 1
(m) xe2x80x94CR15xe2x95x90Nxe2x80x94(CR15R16)bxe2x80x94, where b is 0 or 1
(n) xe2x80x94Nxe2x95x90Nxe2x80x94,
(o) xe2x80x94Nxe2x95x90CR15xe2x80x94(CR15R16)bxe2x80x94, where b is 0 or 1
(p) xe2x80x94CR15xe2x95x90CR15xe2x80x94,
(q) xe2x80x94Nxe2x95x90Nxe2x80x94Yxe2x80x94,
(r) xe2x80x94Yxe2x80x94Nxe2x95x90Nxe2x80x94,
(s) xe2x80x94Yxe2x80x94Nxe2x95x90CR15xe2x80x94, or
(t) xe2x80x94CR5R16xe2x80x94Yxe2x80x94CR15R16xe2x80x94CR15R16xe2x80x94;
E is CR8 or nitrogen;
J is CR15 or nitrogen;
K is
(a) xe2x80x94(CR15R16)axe2x80x94, where a is 2 or 3, or
(b) xe2x80x94CR15xe2x95x90CR15xe2x80x94,
L is
(a) xe2x80x94(CR15R16)axe2x80x94, where a is 2 or 3, or
(b) xe2x80x94Yxe2x80x94(CR15R16)xe2x80x94(CR15R16)xe2x80x94;
Y is oxygen, S(O)m, or NR7;
with the provisos that:
when W is of formula W1; G is C1-4alkyl which is fully saturated and is substituted by hydroxy or morpholinyl, in which morpholinyl is attached through nitrogen; A is CR4; B is CR5; and R8 is hydrogen then at least one of R13, R14, or R7 is not hydrogen or C1-7alkyl;
when W is of formula W1, A is CR4, B is CR5, D is xe2x80x94Yxe2x80x94CR13R14xe2x80x94CR13R14 xe2x80x94, and R8 is hydrogen then Y is not oxygen;
when W is of formula W1, A is CR4, and B is CR5 then D is not xe2x80x94CR15xe2x95x90CR15xe2x80x94;
R4 is H, halogen, or C1-4alkyl optionally substituted by one to three halogens;
R5 is
(a) H,
(b) halo,
(c) OR12,
(d) SR12,
(e) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, or halo,
(f) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR12, SR12, or NR10R11,
(g) (Cxe2x95x90O)R9,
(h) S(O)mR9,
(i) (Cxe2x95x90O)OR2,
(j) NHSO2R9,
(k) nitro, or
(l) cyano;
R7 is
(a) H,
(b) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, or halo,
(c) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR12, SR12, or NR10R11,
(d) aryl,
(e) het,
(f) (Cxe2x95x90O)R9, or
(g) S(O)mR9;
R8 is
(a) H,
(b) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR12, SR12, NR10R11, or halo,
(c) OR12, or
(d) SR12;
R9 is
(a) C1-7alkyl optionally substituted by OR12 or NR2R2,
(b) C3-8cycloalkyl optionally substituted by OR12 or NR2R2,
(c) NR10R11,
(d) aryl, or
(e) het, wherein said het is bound through a carbon atom;
R10 and R11 are independently
(a) H,
(b) aryl,
(c) C1-7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR2R2, CO2R2, het, aryl, cyano, or halo,
(d) C2-7alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR2R2, OR2, or SR2,
(e) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR2, SR2, or NR2R2, or
(f) R10 and R11 together with the nitrogen to which they are attached form a het;
R12 is
(a) H,
(b) aryl,
(c) het
(d) C1-7alkyl optionally substituted by aryl, or halogen,
(e) C2-7alkyl substituted by OR2, SR2, or NR2R2, or
(f) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR2, SR2, or NR2R2;
R13, R14, R15, and R16 are independently
(a) H
(b) C1-7alkyl which may be partially unsaturated and optionally substituted by one or more OR12, SR12, NR10R11, or halo groups,
(c) C3-8cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR12, SR12, or NR10R11,
(d) aryl,
(e) het, wherein said het is bound through a carbon atom,
(f) OR12,
(g) SR12,
(h) NR10R11;
(i) (Cxe2x95x90O)OR2, or
(j) R13 and R14 or R15 and R16 together with the carbon to which they are attached form (Cxe2x95x90O);
each m is independently 0, 1 or 2;
each n is independently 1 or 3;
aryl is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl may be optionally substituted with one or more substituents selected from halo, OH, cyano, NR2R2, CO2R2, CF3, C1-6alkoxy, and C1-6alkyl which maybe further substituted by one to three SR2, NR2R2, OR2, or CO2R2 groups;
het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO2R2, CF3, C1-6alkoxy, oxo, oxime, and C1-6 alkyl which may be further substituted by one to three SR2, NR2R2, OR2, or CO2R2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W and G;
2 represents the point of attachment between W and the carbonyl group of Formula (I);
and pharmaceutically acceptable salts thereof.
In particularly preferred embodiments, X is Cl and G is 4-morpholinylmethyl.
Another embodiment of the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In preferred embodiments, the composition preferably comprises a therapeutically effective amount of the compound or salt.
Still another embodiment of the present invention provides a method for treating a disease or condition in a mammal caused by a viral infection, particularly a herpes viral infection, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
A further embodiment of the present invention comprises the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing diseases or disorders caused by a viral infection, and particularly a herpes viral infection.
A final embodiment of the present invention comprises a method for inhibiting a viral DNA polymerase, comprising contacting (in vitro or in vivo) the polymerase with an effective inhibitory amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
An object of the present invention is to provide novel compounds having biological activity.
A further object of the present invention is to provide novel pharmaceutical compositions.
Still another object of the present invention is to provide a method for treating a disease or condition in a mammal caused by a viral infection, particularly a herpes virus infection.
Another object of the present invention is to provide a method for inhibiting a viral DNA polymerase.
These, and other objects, will readily be apparent to those skilled in the art as reference is made to the detailed description of the preferred embodiment.
In describing the preferred embodiment, certain terminology will be utilized for the sake of clarity. Such terminology is intended to encompass the recited embodiment, as well as all technical equivalents which operate in a similar manner for a similar purpose to achieve a similar result.
1. Terminology Definitions
The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl denotes both straight and branched groups; but reference to an individual radical such as xe2x80x9cpropylxe2x80x9d embraces only the straight chain radical, a branched chain isomer such as xe2x80x9cisopropylxe2x80x9d being specifically referred to. When alkyl can be partially unsaturated, the alkyl chain may comprise one or more (e.g., 1, 2, 3, or 4) double or triple bonds in the chain.
Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic. Het is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated ring containing 1, 2 or 3 heteroatoms selected from the group consisting of non-peroxide oxygen, sulfur, and nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocyclic group. Het includes xe2x80x9cheteroarylxe2x80x9d, which encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3, or 4 heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, C1-4alkyl, phenyl or benzyl.
It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine antiviral activity using the standard tests described herein, or using other similar tests which are well known in the art.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, i.e., the prefix Ci-j indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, C1-7alkyl refers to alkyl of one to seven carbon atoms, inclusive.
The compounds of the present invention are generally named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, xe2x80x9cEtxe2x80x9d for ethyl, xe2x80x9chxe2x80x9d for hour or hours and xe2x80x9crtxe2x80x9d for room temperature).
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. The compounds of the invention include compounds of formula (I) having any combination of the values, specific values, more specific values, and preferred values described herein.
Mammal denotes human and animals, specifically including food animals and companion animals.
2. The Invention
The present invention comprises compounds of formula (I) as defined above, and their pharmaceutically acceptable salts.
For the compounds of formula (I), alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, etc.; C3-8cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl; alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, 1-methylhexyloxy, or heptyloxy; het can be azetidinyl, 3,3-dihydroxy-1-azetinyl, pyrrolidino, piperidino, morpholino, thiomorpholino, or heteroaryl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide).
When alkyl is partially unsaturated, it can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexene-1-ynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl.
Specific examples of W1 include, 
Specific examples of W2 include, 
Specific examples of W3 include: 
Specific examples of W4 include, 
Specific examples of W5 include: 
Specific examples of W6 include: 
Specific examples of W7 include, 
Specific examples of W8 include: 
Particularly preferred compounds are those where X is Cl and G is 4-morpholinylmethyl.
Examples of the present invention include, but are not limited to the following:
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
1-amino-N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5- carboxamide;
1-amino-N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-6-oxo-1,2-dihydro-6H-pyrrolo-[3,2,1-ij]quinoline-5-carboxamide;
1-amino-N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(3-hydroxy-1-propynyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-3-methyl-9-(morpholin-4-ylmethyl)-7-oxo-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-3-methyl-7-oxo-9-(tetrahydro-2H-pyran-4-ylmethyl)-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3-methyl-7-oxo-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-7H-[1,4]thiazino [2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-3-phenyl-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-3-phenyl-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-7-oxo-3-phenyl-9-(tetrahydro-2H-pyran-4-ylmethyl)-1H,7H-[1,3]oxazino [5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-phenyl-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide;
3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide;
1-benzyl-N-(4-chlorobenzyl)-5-(3-hydroxy-1-propynyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
1-benzyl-N-(4-chlorobenzyl)-5-(3-hydroxypropyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
1-benzyl-N-(4-chorobenzyl)-5-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
1-benzyl-N-(4-chlorobenzyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
N-(4-Chlorobenzyl)-5-(3-hydroxyprop-1-ynyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2-(4-morpholinyl)-7-oxo-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2-(4-morpholinyl)-7-oxo-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-2-(4-morpholinyl)-9-(4-morpholinylmethyl)-7-oxo-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-2-(4-morpholinyl)-7-oxo-9-(tetrahydro-2H-pyran-4-methyl)-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-1H,7H-pyrazino[3,2,1-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-1H,7H-pyrazino[3,2,1-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-1H,7H-pyrazino[3,2,1-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-de)quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-2-[(4-chlorobenzyl)amino]-9-(4-morpholinylmethyl)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
2-(benzylamino)-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide;
N-(4-chlorobenzyl)-10-(3-hydroxypropyl)-2,4,8-trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-10-(3-hydroxy-1-propynyl)-2,4,8-trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,4,8-trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5carboxamide;
N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1-[2-(1-piperidinyl)ethyl]-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-1-[2-(4-methyl-1-piperazinyl)ethyl]-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide;
N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-dihydro-2H,8H-[1,4]oxazepino[2,3,4-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-3-methyl-9-(morpholin-4-ylmethyl)-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-3-methyl-7-oxo-9-(tetrahydro-2H-pyran-4-ylmethyl)-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3-methyl-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-7H-[1,4]oxazino [2,3,4-ij]quinoline-6-carboxamide;
N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide;
2-benzyl-N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-3,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[6,7,1-ij]quinoline-7-carboxamide;
N-(4-chlorobenzyl)-5-(3-hydroxypropyl)-4,7-dioxo-1,2-dihydro-4H,7H-imidazo[1,2,3-ij][1,8]naphthyridine-8-carboxamide;
N-(4-chlorobenzyl)-5-(4-morpholinylmethyl)-4,7-dioxo-1,2-dihydro-4H,7H-imidazo[1,2,3-ij][1,8]naphthyridine-8-carboxamide;
N-(4-chlorobenzyl)-5-(3-hydroxy-1-propynyl)-4,7-dioxo-1,2-dihydro-4H,7H-imidazo[1,2,3-ij][1,8]naphthyridine-8-carboxamide;
N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-3-oxo-9,10-dihydro-3H,8H-pyrido [3,2,1-ij]quinoline-2-carboxamide;
N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide hydrobromide;
and pharmaceutically acceptable salts thereof.
Representative examples of the synthesis of compounds falling within the scope of formulas W1-W8 are as follows.
The following Charts A-BQ describe the preparation of the compounds of the present invention. All of the starting materials are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the charts are as defined below or as in the claims.
W1.1. 6-Oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamides The preparation of specific examples of heterocycle W1.1 is described in Chart A. 2-Nitroaniline is iodinated with iodine monochloride to afford A.1 (Wilson, et.al., Aust. J. Chem., 1983, 36, 2317-2326) which is heated with diethyl ethoxymethylenemalonate in a mixture of diphenyl ether/biphenyl, initially at 150xc2x0 C. to generate diethyl 2-[(2-amino-4-iodoanilino)methylene]malonate and then at 240xc2x0 C. to cyclize this intermediate to ethyl 4-hydroxy-6-iodo-8-nitro-3-quinolinecarboxylate (A.2). Stannous chloride reduction of A.2 affords ethyl 8-amino-4-hydroxy-6-iodo-3-quinolinecarboxylate A.3 which reacts with 4-chlorobenzylamine to give 8-amino-N-(4-chlorobenzyl)-4-hydroxy-6-iodo-3-quinolinecarboxamide A.4. Intermediate A.4 reacts with ethyl orthoformate to give N-(4-chlorobenzyl)-8-iodo-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide (A.5). Palladium mediated carbonylation of A.5 in presence of tributyl tin hydride or trioctylsilane (Kotsuki et. al., Synthesis 1996, 470) affords A.6 which is reductively aminated with morpholine and sodium cyanoborohydride to give A.7. Specific examples in which G=3-hydroxypropyl or 3-hydroxy-1-propynyl are prepared as described in Chart B. Palladium catalyzed coupling of A.5 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) gives B.1 (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. or Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula B.2 (Z=CH2OH). 
W1.3. 6-Oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamides. The preparation of specific examples of heterocycle W1.3 is described in Chart C. Condensation of an indoline C.1 (e.g. 2,2-dimethylindoline, R13=2,2-dimethyl) with diethyl ethoxymethylenemalonate followed by cyclization of the resulting enamine C.2 in a mixture of polyphosphoric acid or Eaton""s Reagent affords esters of the formula C.3. Halogenation such as bromination employing bromine in acetic acid provides compounds of the general formula C.4. The resulting product is then coupled with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the corresponding alkynyl derivative C.5. The resulting ester is reacted with a substituted benzylamine (e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or 4-bromobenzylamine) in the presence of sodium methoxide or other appropriate amidation catalyst to afford amides of the formula C.6. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula C.7 (e.g. Z=CH2OH). 
Alternatively, intermediates of the formula C.4 are derivatized as shown in Chart D. The resulting ester is reacted with a substituted benzylamine (e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or 4-bromobenzylamine) in the presence of sodium methoxide or other appropriate amidation catalyst to afford amides of the formula D.1. Coupling of compounds of the formula D.1 with hydroxymethyl(tributyl)stannane (Danheiser, R. L.; Romines, K. R.; Koyama, H. Org. Syn. 1992, 71, 133-139) and a palladium catalyst (e.g. tetrakistriphenylphosphine palladium) affords compounds of the formula D.2. Treatment of the resulting alcohol with methanesulfonyl chloride in the presence of an amine base (e.g. collidine) followed by a primary or secondary amine (HNR1R2, e.g. morpholine) provides compounds of the formula D.3. 
As shown in Chart E, radical bromination of compound C.5 (Rxe2x95x90H) with N-bromosuccinimide, benzoyl peroxide, and carbon tetrachloride affords the benzylic bromide E.1. Displacement of the bromide with excess azide in an appropriate solvent such as DMF or THF at temperatures from 0-100xc2x0 C. provides E.2. Elaboration of the ester to the carboxamide as described in previous examples gives intermediates of the formula E.3. This azide is reduced to give the amine E.4 by treating the azide with triphenylphosphine in THF followed by water hydrolysis of the iminophosphorane intermediate at temperatures from 10-65xc2x0 C. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula E.5 (e.g. Z=CH2OH). The amine can then be alkylated or acylated via conditions well known to those skilled in the art to give analogs defined by NR10R11. 
Alternatively as described in Chart F, intermediate C.3 (Rxe2x95x90H) can be subjected to the same benzylic bromination conditions to give bromide F.1, followed by displacement of the bromide to give the azide F.2. The azide can then be reduced to the amine F.3 as described above and elaborated to the Boc-protected derivative F.4 by treating with di-t-butyldicarbonate and an appropriate base (triethylamine, NaHCO3). Conversion of the ethyl ester to the carboxamide F.6 can be achieved as described in prior examples. Palladium catalyzed carbonylation of the aryl iodide in the presence of tributyltin hydride provides the aryl aldehyde F.7. Reductive amination of F.7 with a primary or secondary amine (e.g. morpholine) and sodium cyanoborohydride affords F.8. Removal of the Boc-group with HCl in dioxane or trifluoroacetic acid results in analog F.9, which can be alkylated or acylated to give a variety of analogs. 
More specifically examples of heterocycle W1.3 are prepared as described in Chart G. Reduction of indoline-2-carboxylic acid (G.1) with borane in THF affords alcohol G.2. Protection of the indoline nitrogen as the benzyl carbamate can be achieved using benzyl chloroformate, THF, and aqueous sodium bicarbonate to give G.3. Iodination using NIS in DMF at elevated temperatures (40-80xc2x0 C.) provides compound G.4. The carbamate is removed using HBr in acetic acid to give acetate G.5, which is cyclized via a two-step protocol using diethyl ethoxymethylenemalonate and Eaton""s Reagent (or polyphosphoric acid) to give G.6. Condensation of this ester with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperatures affords amides of the formula G.7. This material is then coupled with an electron-rich acetylene (e.g. propargyl alcohol) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine or in a mixture of DMF and triethylamine to provide the corresponding alkynyl derivative G.8. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula G.9. 
W1.5. 7-Oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamides. The preparation of specific examples of heterocycle W1.5 is described in Chart H following an established literature precedent (J. Med. Chem. 1988, 31, 991-1001.). Reaction of xcex2-ketoesters of the formula H.1 (prepared as described in Chart J, where Y=iodo; Chart K, where Y=morpholinylmethyl; and Chart L, where Y=4-tetrahydropyranylmethyl) with acetic anhydride and triethylorthoformate followed by treatment of the resulting enol ether with a formyl-substituted hydrazine (e.g. 1-formyl-1-methylhydrazine, R7=methyl, U.S. Pat. No. 5,985,874) affords derivatives of the general formula H.2. Treatment of H.2 with potassium hydroxide followed by formic acid and formaldehyde affords cyclized compounds of the general formula H.3. The resulting carboxylic acid H.3 is then coupled with a benzylamine (e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or 4-bromobenzylamine) mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula H.4. 
As described in Chart I, to prepare derivatives where G=3-hydroxypropyl or 3-hydroxy-1-propynyl, intermediate H.4 (Y=iodo) is further derivatized by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula I.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula I.2 (Z=CH2OH). 
H.1 (Y=iodo) is prepared as described in Chart J. Iodination of 2,3-difluorobenzoic acid J.1 affords 2,3-difluoro-5-iodobenzoic acid J.2. Conversion of J.2 to its corresponding imidazolide with 1,1xe2x80x2-carbonyldiimidazole followed by treatment with the trimethylsilyl ester of ethyl hydrogen malonate in the presence of DBU (Wang, X.; William, T. M.; Napier, J. J.; Ghannam, A. Tetrahedron Lett. 1994, 35, 9323-9326.) provides xcex2-ketoester H.1 (Y=iodo) which may be employed as in Chart H. 
H.1 (Y=morpholinylmethyl) is prepared as described in Chart K. Reductive amination of 3,4-difluoro-4-trifluoromethylbenzaldehyde K.1 with morpholine in the presence of triacetoxyborohydride and acetic acid affords K.2. Hydrolysis of K.2 in sulfuric acid provides carboxylic acid K.3. Conversion of K.3 according to methods analogous to those described in Chart J affords xcex2-ketoester H.1 (Y=morpholinylmethyl) which may be employed as in Chart H. 
H.1 (Y=4-tetrahydropyranylmethyl) is prepared as described in Chart L. Wittig olefination between K.1 and 4-tetrahydropyranylphosphonium bromide (Bestmann, H. J.; Stransky, W.; Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.) employing sodium hexamethyldisilazide as base provides the olefin L.1. Saturation of the olefin by hydrogenation of L.1 employing palladium on carbon as catalyst affords L.2. Hydrolysis of L.2 in sulfuric acid provides carboxylic acid L.3. Conversion of L.3 according to methods analogous to those described in Chart J affords xcex2-ketoester H.1 (Y=4-tetrahydropyranylmethyl) which may be employed as in Chart H. 
W1.6. 7-Oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamides. The preparation of specific examples of heterocycle W1.6 is described in Chart M following an established literature precedent (Bull. Chem. Soc. Jpn. 1996, 69, 1371-1376.). Alcohol AM.4 (Y=morpholinylmethyl, tetrahydropyranylmethyl, or iodo) is treated with thionyl chloride followed by sodium thiol and then sodium hydride to afford the quinoline M.1. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to afford the corresponding amides of the general formula M.2. Specific examples where G=3-hydroxypropyl or 3-hydroxy-1-propynyl are prepared as described in Chart N from intermediate M.2 (Y=iodo) by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula N.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula N.2 (Z=CH2OH). 
W1.7. 7-Oxo-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide. Representative examples of heterocycle W1.7 are prepared as described in Chart O in analogy to reported pyridobenzthiazino ring synthesis (Okada, T. et. al. J. Heterocyclic Chem. 1991, 28, 1067). The reaction of intermediate H.1 (Y=iodo, morpholinylmethyl, or tetrahydropyranylmethyl) with acetic anhydride and triethylorthoformate followed by condensation of the resulting enol ether with an allylic amine (e.g. 3-amino-1-butene, Roberts, J. D.; Mazur, R. H. J. Am. Chem. Soc. 1951, 73, 2509) affords the enamine of formula O.1. Cyclization of O.1 in the presence of a base (e.g. sodium hydride) provides quinolones of the formula O.2. Subsequent ozonolysis affords the carboxaldehyde O.3 which upon treatment with sodium hydrosulfide in DMF provides the tricycle O.4. Treatment of O.4 with thionylchloride followed by lithium chloride promoted elimination at elevated temperatures affords O.5. The resulting ester is saponified under dilute acid conditions and coupled with a benzylamine (e.g. 4-chlorobenzylamine) mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula O.7. In the case where Y=iodo, compounds of the general formula O.7 are further derivatized as described in Chart P. Sonogashira coupling between O.7 (Y=iodo) and an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula P.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula P.2 (Z=CH2OH). 
Additional examples of heterocycle W1.7 are prepared as described in Chart Q. 4-Iodo-2-fluoroaniline (Q.1) is condensed with diethyl ethoxymethylenemalonate under thermal conditions to provide 4-hydroxyquinoline Q.2. The resulting ester is converted to the corresponding amide of the formula Q.3 by either heating with a substituted benzylamine (e.g. 4-chlorobenzylamine), or by saponification of the ester to the acid, activation of the acid using a suitable agent (e.g. 1,1xe2x80x2-carbonyldiimidazole), and condensation with the above substituted benzylamine. The hydroxyquinolines are then reacted with an xcex1-bromo ketones to afford compounds of the formula Q.4 (R is a subset of R15 including optionally substituted alkyl or cycloalkyl, aryl, or het). The resulting ketones are treated with sodium hydrosulfide in DMF to afford compounds of the formula Q.5 directly, or in cases where elimination is not spontaneous, the intermediate alcohol is transformed as described above in Chart O. Intermediate Q.5 is transformed to the corresponding derivatives where G is optionally unsaturated C1-4alkyl substituted by hydroxy in a manner analogous to that previously described in Chart P (P.1, P.2). Alternatively, Q.5 is formylated employing carbon monoxide, a palladium catalyst, and an appropriate reducing agent to provide carboxaldehydes of the formula Q.6. Subsequent reductive amination between Q.6 and a primary or secondary amine (e.g. morpholine) affords compounds of the formula Q.7. 
W1.8. 7-Oxo-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamides. The preparation of specific examples of heterocycle W1.8 is described in Chart R. Hydroxyalkylanilines of the formula R.1 (prepared as described in Chart T when Y=morpholinylmethyl; Chart U when Y=tetrahydropyranylmethyl; Chart U when Y=iodo and R13 is not hydrogen; or according to literature methods when Y=iodo and R13 is hydrogen as described by Cambell, S. F. J. Med. Chem. 1988, 31, 2048-2056.) are condensed with diethyl ethoxymethylenemalonate to provide the corresponding enamine R.2. Acylation of the hydroxyl group employing the conditions of Tani, J. et.al. Chem. Pharm. Bull. 1982, 30, 3517. affords malonate R.3. Cyclization of R.3 under thermal conditions or in a mixture of Eaton""s reagent affords quinoline derivatives of the formula R.4. The resulting ester is then heated with a benzylamine (e.g. 4-chlorobenzylamine) to afford a corresponding carboxamide such as R.5. Treatment of R.5 with an acetal or ketal and p-toluenesulfonic acid in N-methylpyrrolidinone as solvent (EP 373,531) affords tricycles of the formula R.6. Compounds of formula R.5 react with 1,1xe2x80x2-carbonyldiimidazole in DMF to give the 3,7-dioxo-1H,7H-[1,3]oxazino[5,4,3-ij]quinolines of structure R.6 (R13 and R14=O). 
In the case where Y=iodo, the intermediate R.6 is further elaborated as described in Chart S by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the corresponding alkynyl derivatives of formula S.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula S.2 (Z=CH2OH). 
R.1 (Y=morpholinylmethyl) is prepared as described in Chart T. Methyl 3-bromomethyl-6-nitrobenzoate T.1 (Bioorg. Med. Chem. Lett. 1997, 7, 1921.) is treated with morpholine to afford the N-benzylmorpholine T.2. Reduction of the nitro functionality with tin(II) chloride provides the aniline T.3 which is further reduced with diisobutyl aluminum hydride to afford R.1 (Y=morpholinylmethyl, R13=hydrogen). To prepare compounds in which R13 is other than hydrogen, this material can be further elaborated by manganese dioxide oxidation (J. Heterocyclic Chem. 1993, 30, 1533; J. Med. Chem. 1988, 31, 2048) to afford the corresponding carboxaldehyde T.4. The reaction of T.4 with alkyl- or aryllithium and Grignard reagents (e.g. phenyl magnesium bromide) (Aust. J. Chem. 1992, 45, 21.) provides hydroxyanilines R.1 (Y=morpholinylmethyl, R13=optionally substituted alkyl, aryl, or het). 
R.1 (Y=tetrahydropyranylmethyl) is prepared as described in Chart U. Wittig olefination between 3-methylcarboxylate4-nitrobenzaldehyde U.1 (J. Med. Chem. 1988, 41, 1476.) and 4-tetrahydropyranylphosphonium bromide (Bestmann, H. J.; Stransky, W.; Vostrowsky, O. Chem. Ber. 1979, 109, 1694-1700.) employing sodium hexamethyldisilazide as base provides the olefin U.2. Hydrogenation of U.2 catalyzed by palladium on carbon provides the aniline U.3 which is further reduced with diisobutyl aluminum hydride to afford R.1 (Y=tetrahydropyranylmethyl, R13=hydrogen). To prepare compounds in which R13 is other than hydrogen, this material can be further elaborated as above by manganese dioxide oxidation to afford the corresponding carboxaldehyde U.4. The reaction of U.4 with alkyl- or aryllithium and Grignard reagents (e.g. phenyl magnesium bromide) provides hydroxyanilines R.1 (Y=tetrahydropyranylmethyl, R13=optionally substituted alkyl, aryl, or het). 
R.1 (Y=iodo, R13=optionally substituted alkyl, aryl, or het) is prepared as described in Chart V. 2-Hydroxymethyl-4-iodoaniline (R.1, Y=iodo, R13=hydrogen) (Cambell, S. F. J. Med. Chem. 1988, 31, 2048-2056.) is oxidized with manganese dioxide to afford the corresponding carboxaldehyde V.1. The reaction of U.4 with alkyl- or aryl-Grignard reagents (e.g. phenyl magnesium bromide) provides hydroxyanilines R.1 (Y=iodo, R13=optionally substituted alkyl, aryl, or het). 
W1.9. 7-Oxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides. The preparation of specific examples of heterocycle W1.9 is described in Chart X following an established literature precedent (Chem. Pharm. Bull. 1994, 42, 2569.). Reaction of xcex2-ketoesters of the formula H.1 (prepared as described in Chart I, where Y=iodo; Chart J, where Y=morpholinylmethyl; and Chart K, where Y=4-tetrahydropyranylmethyl) with acetic anhydride and triethylorthoformate followed by treatment of the resulting enol ether with an xcex2-aminoalcohol (e.g. 2-aminophenylethanol, Y=phenyl) affords derivatives of the general formula X.1. Cyclization of X.1 in the presence of a sodium carbonate employing N,N-dimethylformamide as solvent provides quinoline X.2. Bromination of the resulting alcohol employing carbon tetrabromide and triphenylphosphine provides alkyl bromide X.3. Hydrolysis of the ester under acidic conditions followed by treatment of the resulting acid X.4 with a primary amine (e.g. methylamine) affords the quinoline X.5. The carboxylic acid is then coupled with a benzylamine (e.g. 4-chlorobenzylamine) mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula X.6. 
To prepare derivatives where G=3-hydroxypropyl or 3-hydroxy-1-propynyl, intermediate X.6 is further derivatized as in Chart Y by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the corresponding alkynyl derivatives of formula Y.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula Y.2 (Z=CH2OH). 
The preparation of other specific examples of heterocycles W1.9 are shown in Charts Y-AD. Compounds of the formula Z.1 (prepared as in Chart AA where Y=morpholinylmethyl; Chart AB where Y=3-hydroxypropyl or 3-hydroxy-1-propynyl) react with oxalyl chloride to afford 2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides of the general formula Z.2. 
Z.1 (Y=morpholinylmethyl) is prepared as described in Chart AA. 2-Nitro-4-methylaniline (AA.1) is heated with diethyl ethoxymethylenemalonate to afford enamine AA.2 which is cyclized by refluxing in Dowtherm A to give 3-quinolinecarboxylate AA.3 (Peet, N. P. J. Med. Chem. 1985, 28, 298-302). Ester AA.3 is reacted with N-bromosuccinimide in 1,2-dichloroethane to give alkyl bromide AA.4. The crude reaction product is treated with morpholine to give AA.5 which is reduced by hydrogenation over palladium on carbon catalyst to provide AA.6. The resulting ester is reacted with a substituted benzylamine (e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or 4-bromobenzylamine) to give amides of the formula Z.1 (Y=morpholinylmethyl) which may be employed as described in Chart Z.
Z.1 (Y=3-hydroxypropyl and 3-hydroxy-1-propynyl) is prepared as described in Chart AB. Sonogashira coupling of A.2 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) provides the alkynyl-substituted quinoline AB.1. Stannous chloride reduction of the nitro group provides the aminoquinoline Z.1. (Y=3-hydroxy-1-propynyl, Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula Z.1 (Y=3-hydroxypropyl, Z=CH2OH). 
Alternatively, compounds of the formula Z.1 (Y=morpholinylmethyl, 3-hydroxypropyl, and 3-hydroxy-1-propynyl) react with bromoacetic anhydride (Rxe2x95x90H) or 2-bromoalkanoyl bromides (e.g. 2-bromopropionyl bromide, R=methyl) to give tricyclic compounds of the formula AC.1, Chart AC. Likewise, compounds of the formula Z.1 (Y=morpholinylmethyl, 3-hydroxypropyl, and 3-hydroxy-1-propynyl) react with ethyl bromoacetate to afford 3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamides according to the general formula AD.1, Chart AD. 
Additional examples of heterocycle W1.9. are prepared as described in Chart AE. The previously described xcex2-ketoester H.1 is reacted with triethyl orthoformate in refluxing acetic anhydride to provide enol ether AE.1, which is further reacted with a mono-tert-butyloxycarbonyl protected ethylenediamine derivitive (where R is defined according to R13) to afford compounds of the formula AE.2. Treatment of AE.2 with cesium carbonate in DMF effects cyclization to afford tricycles of the formula AE.3. Palladium catalyzed carbonylation using carbon monoxide gas and tri-n-butylstannane provides carboxaldehyde AE.4, and subsequent reductive amination with morpholine and sodium triacetoxyborohydride affords compounds of the formula AE.5. Aminolysis of the resulting ester using a substituted benzylamine (e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or 4-bromobenzylamine) in methanol with catalytic sodium methoxide provides AE.6, which is converted to AE.7 on exposure to trifluoromethanesulfonic acid. The nitrogen of the quinoxaline ring in AE.7 may be alkylated, acylated, sulfonylated, etc. giving compounds of formula AE.8. 
Alternatively, esters of the formula AE.3 are reacted with a substituted benzylamine (e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or 4-bromobenzylamine) in methanol employing catalytic sodium methoxide to provide amides of the structure AF.1, which is converted to AF.2 on exposure to trifluoromethanesulfonic acid. The nitrogen of the quinoxaline ring in AF.2 may be alkylated, acylated, sulfonylated, etc. (RN as defined according to R7) giving compounds of formula AF.3. Palladium catalyzed coupling of AF.3 with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) gives AF.4 (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467. or Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AF.5 (Z=CH2OH). 
As described in Chart AG, condensation of AE.1 (Y=iodo, morpholinylmethyl, or tetrahydropyranylmethyl) with a 2-aminoalkanoic amide (e.g. glycine methylamide) followed by treatment with a base such as sodium hydride provides compounds illustrated by formula AG.1. The resulting ester is treated with a benzylamine (e.g. 4-chlorobenzylamine) at high temperature to afford the corresponding carboxamides of the general formula AG.2. In the case where Y=iodo, AG.2 is further derivatived as in Chart AH employing a Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) gives AH.1. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AF.5 (Z=CH2OH). 
W1.10. 7-Oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamides. The preparation of specific examples of heterocycle W1.10 is described in Chart AI following an established literature precedent (Bull Chem. Soc. Jpn. 1996, 69, 1371-1376.). Alcohol AM.4 (Y=morpholinylmethyl, tetrahydropyranylmethyl, or iodo) is treated with thionyl chloride followed by a primary amine to afford quinoline AI.1. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to afford the corresponding amides of the general formula AI.2 Specific examples where G=3-hydroxypropyl or 3-hydroxy-1-propynyl are prepared as described in Chart AJ from intermediate AI.2 (Y=iodo) by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula AJ.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AJ.2 (Z=CH2OH). 
W1.11. 2,7-Dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamides. The preparation of specific examples of heterocycle W1.11 is described in Chart AK following an established literature precedent (Tetrahedron 1995, 51, 11125-11140). Intermediates of the formula AM.3 (Y=iodo, morpholinylmethyl, or tetrahydropyranylmethyl) are saponified under basic conditions and the resulting carboxylic acid is coupled with a substituted benzylamine (e.g. 4-chlorobenzylamine) promoted by 1,1xe2x80x2-carbonyldiimidazole (or another appropriate carboxylic acid activating agent) to provide carboxamides of the general formula AK.1. The resulting carboxamides are treated with 1,3-bis(trimethylsilyl)urea and ethyl malonyl chloride to afford AK.2. Subsequent heating of a DMSO solution of AK.2 in the presence of Cs2CO3 affords the pyridocinnoline AK.3. Hydrolysis and decarboxylation of AK.3 is accomplished by heating AK.2 in a mixture of hydrochloric and acetic acid to afford compounds of the formula AK.4. In the case where Y=iodo, the intermediate AK.4 is further elaborated as described in Chart AL by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the corresponding alkynyl derivatives of formula AL.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AL.2 (Z=CH2OH). 
Other representative examples of heterocycle W1.11 are prepared as described in Chart AM. Ketoester H.1 (Y=iodo, morpholinylmethyl, or tetrahydropyranylmethyl) is condensed with a Boc-protected hydrazine (e.g. tert-butyl 1-methylhydrazinecarboxylate, R7=methyl, prepared as described by Oliva, G. A. et. al. J. Heterocyclic Chem. 2000, 37, 47) to provide derivatives of the formula AM.1. Cyclization of AM.1 in the presence of a base (e.g. sodium hydride) affords quinolones of the general formula AM.2 which are subsequently deprotected using common synthetic methods (Green, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 1999) to provide AM.3. Condensation of AM.3 with formaldehyde provides AM.4. Conversion of the hydroxyl group to an appropriate leaving group such as the chloride upon treatment with thionyl chloride and then subsequent displacement with a malonate diester anion affords quinolone malonates of the formula AM.5. Cyclization of AM.5 by heating in the presence of an inorganic base (e.g. cesium carbonate) provides AM.6. Hydrolysis and decarboxylation of AM.6 is accomplished by initially heating in the presence of an acid (e.g. acetic acid or trifluoroacetic acid) followed by further decarboxylation by heating a DMSO solution to 135-165xc2x0 C. resulting in compounds of the formula AM.7. The resulting carboxylic acid is then coupled with a benzylamine (e.g. 4-chlorobenzylamine) mediated by an appropriate acid activating reagent (e.g. 1,1xe2x80x2-carbonyldiimidazole) to afford carboxamides of the formula AM.8. In the case where Y=iodo, the intermediate AM.8 is further elaborated as described in Chart AN by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the corresponding alkynyl derivatives of formula AN.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AN.2 (Z=CH2OH). 
W1.13. 7-Oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamides. Enol ether AE.1 is reacted with a 2-mercaptoethylamine derivative (where in R is defined according to R13) to afford compounds of the formula AO.1 as a mixture of E/Z isomers. Treatment of AO.1 with cesium carbonate in DMF effects cyclization to benzthiazine AO.2. Aminolysis of the ethyl ester with a substituted benzylamine (e.g. 4-chlorobenzylamine, 4-fluorobenzylamine, or 4-bromobenzylamine) provides amides of the formula AO.3, which are reacted with carbon monoxide and tri-n-butylstannane under palladium catalysis to afford aldehydes of the formula AO.4. Reductive amination of the aldehyde using morpholine and sodium triacetoxyborohydride provides AO.5. Oxidation of the sulfur with meta-chloroperbenzoic acid affords derivatives of the formula AO.6 where n=1 (sulfoxide) or n=2 (sulfone). 
Alternatively, amides of the formula AO.3 are reacted through palladium catalyzed coupling with of an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) to give alkynes of the formula AP.1. Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AP.2 (Z=CH2OH). Oxidation of the sulfur atom found in compounds AP.1 or AP.2 with meta-chloroperbenzoic acid affords sulfoxide (n=1) or sulfone (n=2) derivatives of the formulas AP.3 and AP.4, respectively. 
W1.14. 7-Oxo-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamides. The preparation of specific examples of heterocycle W1.14 is described in Chart AQ. Malonates of the formula R.2 (Y=morpholinylmethyl, tetrahydropyranylmethyl, or iodo) are converted to their corresponding thiolacetate AQ.1 by treatment with triphenylphosphine and diisopropyl azodicarboxylate in the presence of thiolacetic acid (Volante, R. P. Tetrahedron Let. 1981, 22, 3119-3122.). Cyclization of AQ.1 under thermal conditions or in a mixture of Eaton""s reagent affords quinoline derivatives of the formula AQ.2. The resulting ester is then heated with a benzylamine (e.g. 4-chlorobenzylamine) to afford a corresponding carboxamide such as AQ.3. Treatment of AQ.3 with an acetal or ketal and p-toluenesulfonic acid in N-methylpyrrolidinone as solvent (EP 373,531) affords tricycles of the formula AQ.4. 
In the case where Y=iodo, the intermediate AQ.4 is further elaborated as described in Chart AR by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the corresponding alkynyl derivatives of formula AR.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AR.2 (Z=CH2OH). 
W1.15. 7-Oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamides. The preparation of specific examples of heterocycle W1.15 is described in Chart AS. Alkylaminoanilines of the formula AS.1 (prepared as described in Chart AU when Y=morpholinylmethyl, tetrahydropyranylmethyl, or Y=iodo) are condensed with a variety of aldehydes and ketones (e.g. formaldehyde, Rx=Ry=H; benzaldehyde, Rx=phenyl, Ry=H) employing literature methods (Wagner, E. C.; Eisner, A. J. Am. Chem. Soc. 1937, 59, 879-883.; Kempter, G. et.al. J. Prakt. Chem. 1982, 324, 832-840.) to afford tetrahydroquinazolines of the formula AS.2. Condensation of AS.2 with diethyl ethoxymethylenemalonate provides the malonate derivatives AS.3 which are cyclized by heating in a mixture of Eaton""s reagent to afford the substituted quinoline derivatives of the formula AS.4. The resulting ester is then heated with a benzylamine (e.g. 4-chlorobenzylamine) to afford a corresponding carboxamide such as AS.5. 
In the case where Y=iodo, the intermediate AS.5 is further elaborated as described in Chart AT by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the corresponding alkynyl derivatives of formula AT.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AT.2 (Z=CH2OH). 
AS.1 is prepared as described in Chart AU. Hydroxyalkylamines R.1 where Y=morpholinylmethyl, tetrahydropyranylmethyl, or iodo (prepared as described previously in Charts N-P) are oxidized with manganese dioxide or other suitable oxidizing agent to afford the corresponding aldehyde or ketone AU.1. Compounds AU.1 are then converted to the amine derivatives AS.1 by a one step reductive amination employing a primary amine and sodium cyanoborohydride or in a two step sequence involving first formation of the imine by treatment with a primary amine and titanium tetrachloride and then reduction with lithium aluminum hydride (Chem. Pharm. Bull. 1981, 29, 2135.). Alternatively when R7=aryl, compounds of the formula AS.1 (Rz=aryl) are prepared by a Mannich condensation with anilines AU.2 (Y=morpholinylmethyl, tetrahydropyranylmethyl, or iodo) employing procedures described in the literature (Wagner, E. C.; Eisner, A. J. Am. Chem. Soc. 1937, 59, 879-883.). 
Additional representative examples of heterocycle W1.15 are prepared as described in Chart AV. 2-(Hydroxymethyl)-4-methylaniline (AV.1) is condensed with diethyl ethoxymethylenemalonate to afford the enamine AV.2 which is acylated by heating in acetic anhydride to provide enamine AV.3. Cyclization of AV.3 by heating at high temperature in diphenyl ether affords quinoline AV.4. The resulting quinoline was acylated on nitrogen by reaction with isobutyl chloroformate and a base (e.g. sodium hydride) to provide AV.5 which upon irradiation by light in the presence of N-bromosuccinimide and subsequent treatment with a primary or secondary amine (e.g. morpholine) affords compounds illustrated by AV.6. Reductive amination between AV.6 and a primary amine (e.g. benzylamine, R=benzyl) employing a reducing agent such as sodium triacetoxyborohydride affords AV.7. The resulting ester is then heated with a benzylamine (e.g. 4-chlorobenzylamine) to afford a corresponding carboxamide of the formula AV.8. Condensation of AV.8 with formaldehyde affords compounds of the formula AV.9. Alternatively, compounds of the formula AV.8 are condensed with 1,1xe2x80x2-carbonyldiimidazole to provide derivatives of the formula AW.1, Chart AW. 
W1.17. 7-Oxo-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide. The preparation of specific examples of heterocycle W1.17 is described in Chart AX following an established literature precedent (Russ. J. Org. Chem. 1999, 35, 1698-1705). Reaction of xcex2-ketoesters of the formula H.1 (prepared as described in Chart J, where Y=iodo; Chart K, where Y=morpholinylmethyl; and Chart L, where Y=4-tetrahydropyranylmethyl) with acetic anhydride and triethylorthoformate followed by treatment of the resulting enol ether with a substituted thiosemicarbazide (e.g. morpholinothiosemicarbazide, R15=morpholinyl) affords compounds of the formula AX.1. Upon heating AX.1 in benzene, thiadiazinoquinoline AX.2 is provided. The resulting ester is then treated with a benzylamine (e.g. 4-chlorobenzylamine, 4-bromobenzylamine, or 4-fluorobenzylamine) at high temperature to afford the corresponding amides of the general formula AX.3. 
To prepare derivatives where G=3-hydroxypropyl or 3-hydroxy-1-propynyl, intermediate AX.3 (Y=iodo) is further elaborated as in Chart AY by Sonogashira coupling with an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) to provide the corresponding alkynyl derivatives of formula AY.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula AY.2 (Z=CH2OH). 
W1.18. 7-Oxo-2,3-dihydro-1H,7H-pyrazino[3,2,1-ij][1,7]naphthyridine-6-carboxamide. Preparation of specific examples of heterocycles W1.18 follows an established literature precedent (Collect. Czech. Chem. Commun. 1991, 56, 2420) as shown in Chart AZ. 6-Bromo-2-chloro-3-pyridinylamine (AZ.1, J. Med. Chem. 1995, 38, 4830.) is thermally cyclized with methyl 2-(((4-chlorobenzyl)amino)carbonyl)-3-methoxy-2-propenoate to afford AZ.2. The nitrogen is then alkylated in the presence of potassium carbonate and 2-bromo-1-chloroethane in acetone to afford AZ.3. Reaction of AZ.3 with sodium iodide in acetone and treatment of the resulting iodide with sodium azide forms the alkyl azide AZ.4. Reduction of the azide with triphenylphosphine affords the amine AZ.5. The amine is then cyclized thermally to the pyrazine compound AZ.6. The pyrazino compound AZ.6 is then coupled under modified Negishi coupling with vinylzinc in the presence of Pd(PPh3)4 (Palmgren, A.; et.al J. Org. Chem. 1998, 63, 3764), followed by standard functional group manipulation involving oxidative cleavage with osmium tetroxide and sodium periodiate to give the aldehyde AZ.7. This aldehyde is then reacted with morpholine in the presence of acetic acid and sodium cyanoborohydride to afford AZ.8. Alternatively as described in Chart BA, AZ.6 is coupled to an electron-rich alkyne (e.g. propargyl alcohol) through a modified Sonogashira coupling (Linstrumelle, G.; et.al, Tetrahedron Lett, 1993, 34, 6403) to afford BA.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula BA.2 (Z=CH2OH). 
W1.19 7-Oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij][1,7]naphthyridine-6-carboxamides. The preparation of specific examples of heterocycle W1.19 is described in Chart BB. Naphthyridine AZ.3 is reacted with potassium thioacetate in refluxing methanol in the presence of catalytic amount of sodium methoxide to afford BB.1. The thiazino compound BB.1 is then coupled under modified Negishi coupling conditions with vinylzinc in the presence of Pd(PPh3)4 (Palmgren, A.; et.al J. Org. Chem. 1998, 63, 3764), followed by standard functional group manipulation involving oxidative cleavage with osmium tetroxide and sodium periodiate to give the aldehyde BB.2. This aldehyde is then reacted with morpholine in the presence of acetic acid and sodium cyanoborohydride to afford BB.3. Alternatively as described in Chart BC, BB.2 is coupled to an electron-rich alkyne (e.g. propargyl alcohol) through a modified Sonogashira coupling (Linstrumelle, G.; et.al, Tetrahedron Lett, 1993, 34 6403) to afford BC.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula BC.2 (Z=CH2OH). 
W1.20. 7-Oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridine-6-carboxamides. The preparation of specific examples of heterocycle W1.20 is described in Chart BD. Treatment of AZ.3 with sodium iodide in acetone followed by reaction of the resulting intermediate iodide with sodium hydroxide to form the alkoxide which is then cyclized thermally to the oxazine compound BD.1. The oxazino compound BD.1 is then coupled under modified Negishi coupling with vinylzinc in the presence of Pd(PPh3)4 (Palmgren, A.; et.al J. Org. Chem. 1998, 63, 3764), followed by standard functional group manipulation involving oxidative cleavage with osmium tetroxide and sodium periodiate to give the aldehyde BD.2. This aldehyde is then reacted with a primary or secondary amine (e.g. morpholine) in the presence of acetic acid and sodium cyanoborohydride to afford BD.3. Alternatively as described in Chart BE, compound BD.1 is coupled to an electron-rich acetylene (e.g. propargyl alcohol) through a modified Sonogashira coupling (Linstrumelle, G.; et.al, Tetrahedron Lett, 1993, 34 6403) to afford BE.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula BE.2 (Z=CH2OH). 
W1.23. 3,7-Dioxo-3H,7H-pyrido[1,2,3-de] quinoxaline-6-carboxamides. The preparation of specific examples of heterocycle W1.23 is described in Chart BF and Chart BG. Compounds of the formula Z.1 (Y=morpholinylmethyl, 3-hydroxypropyl, or 3-hydroxy-1-propynyl) react with butyl glyoxylate to give pyrido[1,2,3-de]quinoxalines BF.1 (Y=morpholinylmethyl, 3-hydroxy-1-propynyl, or 3-hydroxypropyl). Alternatively, as described in Chart BG compounds of the formula AC.1 react with a primary amine (e.g. 4-chlorobenzylamine, R10=4-chlorobenzyl; benzylamine, R10=benzyl) at high temperature to afford derivatives of the formula BG.1. 
W1.24. 2,4,8-Trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamides. The preparation of specific examples of heterocycle W1.24 is described in Chart BH. Compounds of the formula Z.1 (Y=morpholinylmethyl, 3-hydroxypropyl, or 3-hydroxy-1-propynyl) react with malonyl chloride to give diazepinoquinolines BH.1 (Y=morpholinylmethyl, 3-hydroxy-1-propynyl, or 3-hydroxypropyl). Alternatively, compounds of formula Z.1 react with acryloyl chloride to give diazepinoquinolines of the formula BH.2. 
W1.25. 2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamides. The preparation of specific examples of heterocycle W1.25 is described in Chart BI. Compounds of the formula Z.1 react with 1,1xe2x80x2-carbonyl diimidazole in DMF to give 2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamides BI.1 (Y=morpholinomethyl, 3-hydroxypropyl or 3-hydroxypropynyl) which are converted to the anion with sodium hydride and alkylated with 1-(2-chloroethyl)pyrrolidine or 1-(2-chloroethyl)-4-methylpiperazine to give the products BI.2. 
W1.26. 8-Oxo-3,4-dihydro-2H,8H-[1,4]oxazepino[2,3,4-ij]quinoline-7-carboxamides. The preparation of specific examples of heterocycle W1.26 is shown in Chart BJ. 3-Hydroxy-4-nitrobenzoic acid (BJ.1) is coupled with morpholine to afford amide BJ.2. Alkylation of the phenol with 1-chloro-3-iodopropane yields BJ.3. Catalytic reduction of the nitro group gives aniline BJ.4. Cyclization affords the benzoxazepine BJ.5. Reduction of the amide with lithium aluminum hydride yields BJ.6. Condensation of BJ.6 with diethyl ethoxymethylenemalonate provides BJ.7. Cyclization employing polyphosphoric acid affords ester BJ.8 which is converted to amide BJ.9 by treatment with 4-chlorobenzylamine at elevated temperature. 
W1.52. 7-Oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide. Representative examples of heterocycle W1.52 are prepared as described in Chart BK in analogy to reported pyridobenzoxazino ring synthesis (Augeri, D. J.; Fray, A. H.; Kleinman, E. F. J. Heterocyclic Chem. 1990, 27, 1509). Intermediates of the formula O.3 (Y=iodo, morpholinylmethyl, or tetrahydropyranylmethyl) are treated with a base (e.g. sodium hydride) to afford tricycles of the formula BK.1. The resulting ester is saponified under dilute acid conditions and coupled with a substituted benzylamine (e.g. 4-chlorobenzylamine) mediated by 1,1xe2x80x2-carbonyldiimidazole (or other suitable carboxylic acid activating agent) to provide amides of the general formula BK.3. In the case where Y=iodo, compounds of the general formula BK.3 are further derivatized as described in Chart BL. Sonogashira coupling between BK.3 (Y=iodo) and an electron-rich acetylene (e.g. propargyl alcohol, Z=CH2OH) catalyzed by PdCl2(PPh3)2 and copper(I) iodide either in diethylamine (Sonogashira, K.; Tohada, Y.; Hagihara, N. Tetrahedron Lett. 1975, 50, 4467.) or in a mixture of DMF and triethylamine (Fisher, M. J. et. al. J. Med. Chem. 1997, 40, 2085.) provides the corresponding alkynyl derivatives of formula BL.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of formula BL.2 (Z=CH2OH). 
Alternatively, intermediates of the formula Q.4, cyclize in the presence of a base to afford tricycles of the formula BM.1. Employing conditions analogous to that previously described in Chart BL, intermediate BM.1 is transformed to the corresponding derivatives where G is optionally unsaturated C1-4alkyl substituted by hydroxy (BL.1, BL.2). Alternatively, BM.1 is formylated employing carbon monoxide, a palladium catalyst, and an appropriate reducing agent to provide carboxaldehydes of the formula BM.2. Subsequent reductive amination between BM.2 and a primary or secondary amine (e.g. morpholine) affords compounds of the formula BM.3. 
W1.57. 8-Oxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[6,7,1-ij]quinoline-7-carboxamide. Representative examples of heterocycle W1.57 are prepared as described in Chart BN. Intermediate AV.8 (R is as defined by R7 above for optionally substituted alkyl, optionally substituted cycloalkyl, aryl, or het) is reacted with bromoacetic anhydride and a tertiary amine base (e.g. triethylamine) in N-methylpyrrolidinone to afford compounds of the general formula BN.1. 
W3.1. 4,7-dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamides. The preparation of specific examples of heterocycle W3.1 follows established precedent as shown in Chart BO. 2-Amino-4-bromopyridine (BO.1) is reacted with Boc-anhydride in dichloromethane to afford the Boc-protected amine BO.2 which is then oxidized with peroxybenzoic acid (Justus Liebigs Ann. Chem. 1972, 758, 111) to provide BO.3. The nitrogen is then alkylated with 2-bromoethyl trimethylsilyl ether in the presence of potassium carbonate in acetone to provide BO.4. The Boc group is then removed under standard deprotection conditions to afford BO.5. The pyrimidone BO.5 is then cyclized with methyl 2-(((4-chlorobenzyl)amino)carbonyl)-3-methoxy-2-propenoate to give BO.6. Deprotection of the TMS ether followed by alkylation under Mitsunobu conditions (triphenyl phosphine and DEAD) affords BO.7. Naphthyridine BO.7 is then coupled under modified Negishi coupling with vinylzinc in the presence of Pd(PPh3)4 (Palmgren, A.; et.al J. Org. Chem. 1998, 63, 3764), followed by standard functional group manipulation involving oxidative cleavage with osmium tetroxide and sodium periodiate to give the aldehyde BO.8. This aldehyde is then reacted with a primary or secondary amine (e.g. morpholine) in the presence of acetic acid and sodium cyanoborohydride to afford BO.9. 
Specific examples in which G=3-hydroxypropyl or 3-hydroxy-1-propynyl are prepared as described in Chart BP. Bromide BO.8 is coupled with an electron-rich acetylene (e.g. propargyl alcohol) through a modified Sonogashira coupling (Linstrumelle, G.; et.al, Tetrahedron Lett, 1993, 34 6403) to afford BP.1 (Z=CH2OH). Saturation of the alkyne by hydrogenation catalyzed by palladium on carbon in alcoholic solvents affords alkyl derivatives of the formula BP.2 (Z=CH2OH). 
W4.1. 3-Oxo-9,10-dihydro-3H,8H-pyrido[3,2,1-ij]quinoline-2-carboxamides. The preparation of specific examples of heterocycle W4.1 is described in Chart BQ. Reduction of 5,6,7,8-tetrahydroquinoline-3-carbonitrile (BQ.1) with DIBAL affords the corresponding carboxaldehyde BQ.2. Reductive amination between BQ.2 and a secondary amine (e.g. morpholine) affords a pyridyl derivative such as BQ.3. Treatment of BQ.3 with tert-butyl lithium followed by condensation of the resulting anion with diethyl ethoxymethylenemalonate provides the malonate BQ.4. Subsequent cyclization mediated by triethylamine affords BQ.5, and the resulting ester is condensed with a substituted benzylamine (e.g. 4-chlorobenzylamine) mediated by trimethylaluminum to afford a corresponding carboxamide of the formula BQ.6. 
The inventive compounds may be used in their native form or as salts. In cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, glutarate, and glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
Compounds of the present invention can conveniently be administered in a pharmaceutical composition containing the compound in combination with a suitable excipient, the composition being useful in combating viral infections. Pharmaceutical compositions containing a compound appropriate for antiviral use are prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington""s Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed., 1975). The compounds and compositions of the present invention can be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically (including but not limited to surface treatment, transdermal application, and nasal application), intravaginally, orally, or rectally, depending on whether the preparation is used to treat internal or external viral infections.
For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices such as the osmotic release type devices developed by the Alza Corporation under the OROS trademark.
The compounds or compositions can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
The compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
For internal infections, the compositions can be administered orally or parenterally at dose levels, calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and can be used in man in a unit dosage form, administered one to four times daily in the amount of 1 to 1000 mg per unit dose.
For parenteral administration or for administration as drops, as for eye infections, the compounds are presented in aqueous solution in a concentration of from about 0.1 to about 10%, more preferably about 0.1 to about 7%. The solution may contain other ingredients, such as emulsifiers, antioxidants or buffers.
Generally, the concentration of the compound(s) of formula I in a liquid composition, such as a lotion, will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%. The concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%.
The exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment and, of course, the judgment of the attending practitioner. The compounds of the present invention can be administered to an animal in need of treatment. In most instances, this will be a human being, but the treatment of livestock and companion animals is also specifically contemplated as falling within the scope of the instant invention.
The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful as antiviral agents. Thus, they are useful to combat viral infections in animals, including man. The compounds are generally active against herpes viruses, and are particularly useful against the varicella zoster virus, the Epstein-Barr Virus, the herpes simplex virus types 1 and 2 (HSV-1 and 2), the human herpes virus types 6, 7 and 8 (HHV-6, 7 and 8) and the human cytomegalovirus (HCMV).